Schizophrenia is a psychotic disorder associated with positive, negative, and cognitive symptoms, neuropsychological deficits, and poor social functioning. Classical theories of schizophrenia have focused on abnormal dopaminergic neurotransmission, and clinical treatments for schizophrenia include use of the typical (“first generation”) and atypical (“second generation”) antipsychotics, which function in part as dopamine antagonists. Examples of typical antipsychotics (or neuroleptics) include chlorpromazine, haloperidol, fluphenazine, and thioridazine. Examples of atypical antipsychotic include clozapine, risperidone, olanzapine, quetiapine, ziprasidone, aripiprazole, and sertindole.
Recent theories have postulated that schizophrenia is associated with dysfunction or dysregulation of neurotransmission mediated at brain N-methyl-D-aspartate (NMDA)-type glutamate receptors (Javitt, D. C. and Zukin, S. R., Am. J. Psychiatry 1991, 148, 1301-1308; Javitt, U.S. Pat. No. 5,837,730; Javitt et al., U.S. Pat. No. 5,854,286; Javitt, U.S. Pat. No. 6,162,827; Javitt, U.S. Pat. No. 6,355,681; Javitt, U.S. Pat. No. 6,361,957; Tsai and Coyel, U.S. Pat. No. 6,667,297; Tsai and Coyel, U.S. Pat. No. 6,974,821; Javitt, U.S. Application Publication No. 2002/0010212; Javitt, U.S. Application Publication No. 2002/0013364; Tsai and Coyel, U.S. Application Publication No. 2002/0035145; U.S. Application Publication No. 2002/0161048; Javitt, U.S. Application Publication No. 2002/0183390; Tsai and Coyel, U.S. Application Publication No. 2002/0193429; Tsai and Coyel, U.S. Application Publication No. 2004/0092530; Javitt, U.S. Application Publication No. 2005/0159488; and Tsai and Coyet, U.S. Application Publication No. 2005/0250851). NMDA glycine-site agonists (including glycine, D-serine, and D-alanine) and partial agonists (e.g., D-cycloserine) induce significant improvement in negative and cognitive symptoms in schizophrenics (Javitt et al., Am. J. Psychiatry 1994, 151, 1234-1236; Heresco-Levy et al., Br. J. Psychiatry 1996, 169, 610-617; Heresco-Levy et al., Arch. Gen. Psychiatry 1999, 56, 29-36; Heresco-Levy et al., Am. J. Psychiatry 2002, 159, 480-482; Goff, et al., Am. J. Psychiatry 1995, 152, 1213-1215; Goff et al., Arch. Gen. Psychiatry 1999, 56, 21-27; van Berckel et al., Biol. Psychiatry 1996, 40, 1298-1300; Tsai et al., Biol. Psychiatry 1998, 44, 1081-1089; and Tsai et al., Biol. Psychiatry 2006, 59, 230-234, each of which is incorporated by reference herein in its entirety), supporting the role of glutamatergic hypofunctioning in this psychotic disorder. While clinical studies of schizophrenia using NMDA agonists as single agents have been undertaken (e.g., van Berckel et al., Biol. Psychiatry 1996, 40, 1298-1300), in the majority of the published studies these compounds were administered adjunctively with either conventional neuroleptics or atypical antipsychotic drugs to augment the activity of standard therapies.
Synaptic levels of the endogenous agonists for the NMDA receptor glycine site, for example, glycine and D-serine, are regulated in the mammalian brain by the activity of reuptake transporters. Inhibition of such transporters can potentiate signaling by the endogenous agonist and can provide an alternative to direct administration of the agonist itself. High affinity glycine transporters are encoded by two separate genes: GLYT1 and GLYT2 (Supplisson et al., FEBS Lett. 2002, 529, 93-101). GLYT1 is expressed abundantly in glial cells and is believed to be a primary regulator of glycine concentrations at the NMDA receptor. Sarcosine (N-methylglycine) is a transported, competitive inhibitor of GLYT1 that has been dosed adjunctively with typical and atypical antipsychotic agents and is shown to improve positive, negative, and cognitive symptom domains in schizophrenic patients (Tsai et al., Biol. Psychiatry 2004, 55, 452-456; and Lane et al., Arch. Gen. Psychiatry 2005, 62, 1196-1204).
1-Aminocyclopropanecarboxylic acid is frequently characterized in the literature as an NMDA partial agonist acting at the glycine site, although a recent detailed mechanistic analysis supports concurrent high affinity, fully efficacious agonist activity at the glycine site and lower affinity antagonist activity at the glutamate binding site of the NMDA heterodimer (Nahum-Levy et al., Mol. Pharmacol. 1999, 56, 1207-1218). The utility of 1-aminocyclopropanecarboxylic acid as therapy for a variety of neurodegenerative and neuropsychiatric disorders is predicated on its functional antagonism of NMDA neurotransmission at relatively high doses (Trullas and Skolnick., U.S. Pat. No. 5,086,072; Skolnick et al., U.S. Pat. No. 5,428,069; Maccecchini, U.S. Pat. No. 5,523,323; Skolnick et al., U.S. Pat. No. 6,017,957; Schneider, U.S. Application Publication No. 2004/0087596; Davis and Ressler, U.S. Application Publication No. 2004/0208923; and Davis and Ressler, U.S. Application Publication No. 2005/0096396).
The sub-optimal biopharmaceutical properties of α-amino acid NMDA glycine-site agonists such as glycine, D-serine, D-alanine, and 1-aminocyclopropanecarboxylic acid, and GLYT1 inhibitors such as sarcosine can significantly limit the clinical utility of these agents in the treatment of schizophrenia and other CNS disorders. Glycine has limited blood-brain-barrier permeability and enormous doses (about 30-60 g/day) must be administered to produce a beneficial effect in schizophrenics. While oral therapy with D-serine and sarcosine has allowed for more pharmaceutically practical doses (about 2 g/day), the intrinsically rapid clearance of these amino acids has necessitated frequent daily administration (t.i.d), providing a therapeutic regimen that discourages compliance and is inconvenient for patients. Moreover, the short half-lives of these amino acids ensure that plasma levels fluctuate widely, potentially limiting exposure to optimum therapeutic levels throughout the day.
This disclosure satisfies an unmet need for new medicinal agents that can provide for stimulation of NMDA receptor signaling pathways and are suitable for administration to patients in need of such therapy once daily or multiple times daily. Such compounds, and pharmaceutical compositions comprising the compounds, can be useful for the treatment of, for example, positive, negative, and/or cognitive symptom domains in schizophrenics, and may be administered alone or adjunctive to other antipsychotic medicaments. These compounds, and pharmaceutical compositions comprising the compounds, can also be useful for treatment of other neuropsychiatric and neurodegenerative diseases such as dementia, depression, attention-deficit disorders, learning and memory disorders, and other diseases where NMDA-mediated neurotransmission is implicated.